Compounds and compositions for delivering active agents

ABSTRACT

Compounds and compositions for the delivery of active agents are provided. Methods of administration and preparation are provide as well.

FIELD OF THE INVENTION

[0001] The present invention relates to compounds for delivering activeagents, such as biologically or chemically active agents, to a target.These compounds are well suited for forming non-covalent mixtures withactive agents for oral, intracolonic, pulmonary, or other routes ofadministration to animals. Methods for the preparation andadministration of such compositions are also disclosed.

BACKGROUND OF THE INVENTION

[0002] Conventional means for delivering active agents are oftenseverely limited by biological, chemical, and physical barriers.Typically, these barriers are imposed by the environment through whichdelivery occurs, the environment of the target for delivery, and/or thetarget itself. Biologically and chemically active agents areparticularly vulnerable to such barriers.

[0003] In the delivery to animals of biologically active and chemicallyactive pharmacological and therapeutic agents, barriers are imposed bythe body. Examples of physical barriers are the skin, lipid bi-layersand various organ membranes that are relatively impermeable to certainactive agents but must be traversed before reaching a target, such asthe circulatory system. Chemical barriers include, but are not limitedto, pH variations in the gastrointestinal (GI) tract and degradingenzymes.

[0004] These barriers are of particular significance in the design oforal delivery systems. Oral delivery of many biologically or chemicallyactive agents would be the route of choice for administration to animalsif not for biological, chemical, and physical barriers. Among thenumerous agents which are not typically amenable to oral administrationare biologically or chemically active peptides, such as calcitonin andinsulin; polysaccharides, and in particular mucopolysaccharidesincluding, but not limited to, heparin; heparinoids; antibiotics; andother organic substances. These agents may be rapidly renderedineffective or destroyed in the gastro-intestinal tract by acidhydrolysis, enzymes, and the like. In addition, the size and structureof macromolecular drugs may prohibit absorption.

[0005] Earlier methods for orally administering vulnerablepharmacological agents have relied on the co-administration of adjuvants(e.g., resorcinols and non-ionic surfactants such as polyoxyethyleneoleyl ether and n-hexadecylpolyethylene ether) to increase artificiallythe permeability of the intestinal walls, as well as theco-administration of enzymatic inhibitors (e.g., pancreatic trypsininhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibitenzymatic degradation. Liposomes have also been described as drugdelivery systems for insulin and heparin. However, broad spectrum use ofsuch drug delivery systems is precluded because: (1) the systems requiretoxic amounts of adjuvants or inhibitors; (2) suitable low molecularweight cargos, i.e. active agents, are not available; (3) the systemsexhibit poor stability and inadequate shelf life; (4) the systems aredifficult to manufacture; (5) the systems fail to protect the activeagent (cargo); (6) the systems adversely alter the active agent; or (7)the systems fail to allow or promote absorption of the active agent.

[0006] More recently, proteinoid microspheres have been used to deliverpharmaceuticals. For example, see U.S. Pat. No. 5,401,516, U.S. Pat. No.5,443,841 and U.S. Pat. No. RE35,862. In addition, certain modifiedamino acids have been used to deliver pharmaceuticals. See, e.g., U.S.Pat. No. 5,629,020; U.S. Pat. No. 5,643,957; U.S. Pat. No. 5,766,633;U.S. Pat. No. 5,776,888; and U.S. Pat. No. 5,866,536.

[0007] However, there is still a need for simple, inexpensive deliverysystems which are easily prepared and which can deliver a broad range ofactive agents by various routes.

SUMMARY OF THE INVENTION

[0008] Compounds and compositions that are useful in the delivery ofactive agents are provided. The present invention encompasses compoundshaving the following formula, or salts thereof, or mixtures thereof.

[0009] The compositions of the present invention comprise at least oneactive agent, preferably a biologically or chemically active agent, andat least one of the compounds, or salts thereof, of the presentinvention. Methods for the preparation and administration of suchcompositions are also provided.

[0010] Also provided are dosage unit forms comprising the compositions.The dosage unit form may be in the form of a solid (such as a tablet,capsule or particle such as a powder or sachet) or a liquid.

[0011] Methods for administering a biologically active agent to ananimal in need of the agent, especially by the oral, intracolonic orpulmonary routes, with the compositions of the present invention, arealso provided, as well as methods of treatment using such compositions.A method of treating a disease in an animal comprising administering acomposition of the present invention to the animal in need thereof isprovided.

DETAILED DESCRIPTION OF THE INVENTION

[0012] Compounds

[0013] The compounds may be in the form of the carboxylic acid and/ortheir salts. Salts include but are not limited to organic and inorganicsalts, for example alkali-metal salts, such as sodium, potassium andlithium; alkaline-earth metal salts, such as magnesium, calcium orbarium; ammonium salts; basic amino acids such as lysine or arginine;and organic amines, such as dimethylamine or pyridine. Preferably, thesalts are sodium salts. The salts may be mono- or multi-valent salts,such as monosodium salts and di-sodium salts. The salts may also besolvates including ethanol solvates.

[0014] In addition, poly amino acids and peptides comprising one or moreof these compound may be used.

[0015] An amino acid is any carboxylic acid having at least one freeamine group and includes naturally occurring and synthetic amino acids.Poly amino acids are either peptides (which are two or more amino acidsjoined by a peptide bond) or are two or more amino acids linked by abond formed by other groups which can be linked by, e.g., an ester or ananhydride linkage. Peptides can vary in length from dipeptides with twoamino acids to polypeptides with several hundred amino acids. One ormore of the amino acids or peptide units may be acylated or sulfonated.

[0016] The compounds described herein may be derived from amino acidsand can be readily prepared from amino acids by methods within the skillof those in the art based upon the present disclosure and the methodsdescribed in WO96/30036, WO97/36480, U.S. Pat. No. 5,643,957 and U.S.Pat. No. 5,650,386. For example, the compounds may be prepared byreacting the single amino acid with the appropriate acylating oramine-modifying agent, which reacts with a free amino moiety present inthe amino acid to form amides. Protecting groups may be used to avoidunwanted side reactions as would be known to those skilled in the art.With regard to protecting groups, reference is made to T. W. Greene,Protecting Groups in Organic Synthesis, Wiley, N.Y. (1981), thedisclosure of which is hereby incorporated herein by reference.

[0017] Salts of the present compound may be made by methods known in theart. For example, sodium salts may be made by dissolving the compound inethanol and adding aqueous sodium hydroxide.

[0018] The compound may be purified by recrystallization or byfractionation on one or more solid chromatographic supports, alone orlinked in tandem. Suitable recrystallization solvent systems include,but are not limited to, acetonitrile, methanol, and tetrahydrofuran.Fractionation may be performed on a suitable chromatographic supportsuch as alumina, using methanol/n-propanol mixtures as the mobile phase;reverse phase chromatography using trifluoroacetic acid/acetonitrilemixtures as the mobile phase; and ion exchange chromatography usingwater or an appropriate buffer as the mobile phase. When anion exchangechromatography is performed, preferably a 0-500 mM sodium chloridegradient is employed.

[0019] According to one embodiment, the compound is employed in itsanhydrous form.

[0020] Active Agents

[0021] Active agents suitable for use in the present invention includebiologically active agents and chemically active agents, including, butnot limited to, pesticides, pharmacological agents, and therapeuticagents.

[0022] For example, biologically or chemically active agents suitablefor use in the present invention include, but are not limited to,proteins; polypeptides; peptides; hormones; polysaccharides, andparticularly mixtures of muco-polysaccharides; carbohydrates; lipids;other organic compounds; and particularly compounds which by themselvesdo not pass (or which pass only a fraction of the administered dose)through the gastro-intestinal mucosa and/or are susceptible to chemicalcleavage by acids and enzymes in the gastro-intestinal tract; or anycombination thereof.

[0023] Further examples include, but are not limited to, the following,including synthetic, natural or recombinant sources thereof: growthhormones, including human growth hormones (hGH), recombinant humangrowth hormones (rhGH), bovine growth hormones, and porcine growthhormones; growth hormone-releasing hormones; interferons, including α, βand γ; interleukin-1; interleukin-2; insulin, including porcine, bovine,human, and human recombinant, optionally having counter ions includingsodium, zinc, calcium and ammonium; insulin-like growth factor,including IGF-1; heparin, including unfractionated heparin, heparinoids,dermatans, chondroitins, low molecular weight heparin, very lowmolecular weight heparin and ultra low molecular weight heparin;calcitonin, including salmon, eel, porcine and human; erythropoietin;atrial naturetic factor; antigens; monoclonal antibodies; somatostatin;protease inhibitors; adrenocorticotropin, gonadotropin releasinghormone; oxytocin; leutinizing-hormone-releasing-hormone; folliclestimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim;prostaglandins; cyclosporin; vasopressin; cromolyn sodium (sodium ordisodium chromoglycate); vancomycin; desferrioxamine (DFO); parathyroidhormone (PTH), including its fragments; antimicrobials, includinganti-fungal agents; vitamins; analogs, fragments, mimetics orpolyethylene glycol (PEG)-modified derivatives of these compounds; orany combination thereof. Other suitable forms of insulin, including, butnot limited to, synthetic forms of insulin, are described in U.S. Pat.Nos. 4,421,685, 5,474,978, and 5,534,488, each of which is herebyincorporated by reference in its entirety.

[0024] Delivery Systems

[0025] The compositions of the present invention comprise a deliveryagent and one or more active agents. In one embodiment, one or more ofthe delivery agent compounds, or salts of these compounds, or poly aminoacids or peptides of which these compounds or salts form one or more ofthe units thereof, may be used as a delivery agent by mixing with theactive agent prior to administration.

[0026] The administration compositions may be in the form of a liquid.The dosing vehicle may be water (for example, for salmon calcitonin,parathyroid hormone, and erythropoietin), 25% aqueous propylene glycol(for example, for heparin) and phosphate buffer (for example, for rhGH).Other dosing vehicles include polyethylene glycols, sorbitol, maltitol,and sucrose. Dosing solutions may be prepared by mixing a solution ofthe delivery agent compound with a solution of the active agent, justprior to administration. Alternately, a solution of the delivery agent(or active agent) may be mixed with the solid form of the active agent(or delivery agent). The delivery agent compound and the active agentmay also be mixed as dry powders. The delivery agent compound and theactive agent can also be admixed during the manufacturing process.

[0027] The dosing solutions may optionally contain additives such asphosphate buffer salts, citric acid, glycols, or other dispersingagents. Stabilizing additives may be incorporated into the solution,preferably at a concentration ranging between about 0.1 and 20% (w/v).

[0028] The administration compositions may alternately be in the form ofa solid, such as a tablet, capsule or particle, such as a powder orsachet. Solid dosage forms may be prepared by mixing the solid form ofthe compound with the solid form of the active agent. Alternately, asolid may be obtained from a solution of compound and active agent bymethods known in the art, such as freeze drying, precipitation,crystallization and solid dispersion.

[0029] The administration compositions of the present invention may alsoinclude one or more enzyme inhibitors. Such enzyme inhibitors include,but are not limited to, compounds such as actinonin or epiactinonin andderivatives thereof. Other enzyme inhibitors include, but are notlimited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.

[0030] The amount of active agent used in an administration compositionof the present invention is an amount effective to accomplish thepurpose of the particular active agent for the target indication. Theamount of active agent in the compositions typically is apharmacologically, biologically, therapeutically, or chemicallyeffective amount. However, the amount can be less than that amount whenthe composition is used in a dosage unit form because the dosage unitform may contain a plurality of compound/active agent compositions ormay contain a divided pharmacologically, biologically, therapeutically,or chemically effective amount. The total effective amount can then beadministered in cumulative units containing, in total, an effectiveamount of the active agent.

[0031] The total amount of active agent to be used can be determined bymethods known to those skilled in the art. However, because thecompositions may deliver active agents more efficiently than priorcompositions, lower amounts of biologically or chemically active agentsthan those used in prior dosage unit forms or delivery systems can beadministered to the subject, while still achieving the same blood levelsand/or therapeutic effects.

[0032] The presently disclosed compounds deliver biologically andchemically active agents, particularly in oral, intranasal, sublingual,intraduodenal, subcutaneous, buccal, intracolonic, rectal, vaginal,mucosal, pulmonary, transdermal, intradermal, parenteral, intravenous,intramuscular and ocular systems, as well as traversing the blood-brainbarrier.

[0033] Dosage unit forms can also include any one or combination ofexcipients, diluents, disintegrants, lubricants, plasticizers,colorants, flavorants, taste-masking agents, sugars, sweeteners, salts,and dosing vehicles, including, but not limited to, water, 1,2-propanediol, ethanol, olive oil, or any combination thereof.

[0034] The compounds and compositions of the subject invention areuseful for administering biologically or chemically active agents to anyanimals, including but not limited to birds such as chickens; mammals,such as rodents, cows, pigs, dogs, cats, primates, and particularlyhumans; and insects.

[0035] The system is particularly advantageous for delivering chemicallyor biologically active agents that would otherwise be destroyed orrendered less effective by conditions encountered before the activeagent reaches its target zone (i.e. the area in which the active agentof the delivery composition is to be released) and within the body ofthe animal to which they are administered. Particularly, the compoundsand compositions of the present invention are useful in orallyadministering active agents, especially those that are not ordinarilyorally deliverable, or those for which improved delivery is desired.

[0036] The compositions comprising the compounds and active agents haveutility in the delivery of active agents to selected biological systemsand in an increased or improved bioavailability of the active agentcompared to administration of the active agent without the deliveryagent. Delivery can be improved by delivering more active agent over aperiod of time, or in delivering active agent in a particular timeperiod (such as to effect quicker or delayed delivery) or over a periodof time (such as sustained delivery).

[0037] Following administration, the active agent present in thecomposition or dosage unit form is taken up into the circulation. Thebioavailability of the agent is readily assessed by measuring a knownpharmacological activity in blood, e.g. an increase in blood clottingtime caused by heparin, or a decrease in circulating calcium levelscaused by calcitonin. Alternately, the circulating levels of the activeagent itself can be measured directly.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] The following examples illustrate the invention withoutlimitation. All parts are given by weight unless otherwise indicated.

EXAMPLE 1

[0039] Compound Preparation

[0040] 1a. Preparation of Compound 1.

[0041] 4-Chlorosalicylic acid (10.0 g, 0.0579 mol) was added to aone-neck 250 ml round-bottomed flask containing about 50 ml methylenechloride. Stirring was begun and continued for the remainder of thereaction. Coupling agent 1,1-carbonyldiimidazole (9.39 g, 0.0579 mol)was added as a solid in portions to the flask. The reaction was stirredat room temperature for approximately 20 minutes after all of thecoupling agent had been added and then ethyl-4-aminobutyratehydrochloride (9.7 g, 0.0579 mol) was added to the flask with stirring.Triethylamine (10.49 ml, 0.0752 mol) was added dropwise from an additionfunnel. The addition funnel was rinsed with methylene chloride. Thereaction was allowed to stir at room temperature overnight.

[0042] The reaction was poured into a separatory funnel and washed with2N HCl and an emulsion formed. The emulsion was left standing for twodays. The emulsion was then filtered through celite in a fritted glassfunnel. The filtrate was put back in a separatory funnel to separate thelayers. The organic layer was dried over sodium sulfate, which was thenfiltered off and the filtrate concentrated by rotary evaporation. Theresulting solid material was hydrolyzed with 2N NaOH, stored overnightunder refrigeration, and then hydrolyzing resumed. The solution wasacidified with 2N HCl and the solids that formed were isolated, driedunder vacuum, and recrystallized twice using methanol/water. Solidsprecipitated out overnight and were isolated and dried. The solids weredissolved in 2N NaOH and the pH of the sample was brought to pH 5 with2N HCl. The solids were collected and HPLC revealed a single peak. Thesesolids were then recrystallized in methanol/water, isolated, and thendried under vacuum, yielding 4.96 g (33.0%) of 4-(4chloro-2-hydroxybenzoyl)aminobutyric acid. (C₁₁H₁₂ClNO₄; Molecularweight 257.67.) Melting point: 131-133° C. Combustion analysis: %C:51.27(calc.), 51.27 (found); %H: 4.69 (calc.), 4.55 (found); %N: 5.44(calc.), 5.30 (found). H NMR Analysis: (d₆-DMSO): δ 13.0, s, 1H (COOH);δ 12.1, s, 1H (OH); δ 8.9, t, 1H (NH); δ 7.86, d, 1H (H ortho to amide);δ 6.98, d, 1H (H ortho to phenol OH); δ 6.96, d, 1H, (H meta to amide);δ 3.33, m, 2H (CH₂ adjacent to NH); δ 2.28, t, 2H (CH₂ adjacent toCOOH); 67 1.80, m, 2H (aliphatic CH₂ beta to NH and CH₂ beta to COOH)

[0043] 1b. Additional Preparation of Compound 1.

[0044] 4-Chlorosalicylic acid (25.0 g, 0.1448 mol) was added to aone-neck 250 ml round-bottomed flask containing about 75-100 mlmethylene chloride. Stirring was begun and continued to the remainder ofthe reaction. Coupling agent 1,1-carbonyldiimidazole (23.5 g, 0.1448mol) was added as a solid in portions to the flask. The reaction wasstirred at room temperature for approximately 20 minutes after all ofthe coupling agent had been added and then ethyl-4-aminobutyratehydrochloride (24.3 g 0.1448 mol) was added to the flask with stirring.Triethylamine (26.0 ml, 0.18824 mol) was added dropwise from an additionfunnel. The addition funnel was rinsed with methylene chloride. Thereaction was allowed to stir at room temperature overnight.

[0045] The reaction was poured into a separatory funnel and washed with2N HCl and an emulsion formed. The emulsion was filtered through celitein a fritted glass funnel. The filtrate was put back in a separatoryfunnel to separate the layers. The organic layer was washed with waterand brine, then dried over sodium sulfate, which was then filtered offand the filtrate concentrated by rotary evaporation. The resulting solidmaterial was hydrolyzed with 2N NaOH overnight. The solution wasacidified with 2N HCl and the brown solids that formed wererecrystallized using methanol/water, hot filtering off insoluble blackmaterial. White solids precipitated out and were isolated and dried,yielding 11.68 g (37.0%)of 4-(4 chloro-2-hydroxybenzoyl)aminobutyricacid. (C₁₁H₁₂ClNO₄; Molecular weight 257.67.) Melting point: 129-133° C.Combustion analysis: %C: 51.27(calc.), 51.26 (found); %H: 4.69 (calc.),4.75 (found); %N: 5.44 (calc.), 5.32 (found). H NMR Analysis: (d₆-DMSO):δ 13.0, s, 1H (COOH); δ 12.1, s, 1H (OH); δ 8.9, t, 1H (NH); δ 7.86, d,1H (H ortho to amide); 67 6.98, d, 1H (H ortho to phenol OH); δ 6.96, d,1H, (H meta to amide); δ 3.33, m, 2H (CH₂ adjacent to NH); δ 2.28, t, 2H(CH₂ adjacent to COOH); δ 1.80, m, 2H (aliphatic CH₂ beta to NH and CH₂beta to COOH)

[0046] 1c. Additional Preparation of Compound 1

[0047] (4-[(4-Chloro-2-hydroxybenzoyl)amino]butanoic acid)

[0048] A 22 L, five neck, round bottom flask was equipped with anoverhead stirrer, 1 L Dean-Stark trap with reflux condenser,thermocouple temperature read out, and heating mantle. The followingreaction was run under a dry nitrogen atmosphere. Reagent n-butanol(5000 mL) and 4-chlorosalicylic acid (2000 g, 11.59 mol) were charged tothe reaction flask. The Dean-Stark trap was filled with n-butanol (1000mL). Concentrated sulfuric acid (50 g) was added. The reaction mixturewas heated to reflux for approximately 120 hours. Approximately 206 mLwater was collected in the trap during this time. The heating mantle wasremoved and the reaction mixture allowed to cool to ambient temperature.The Dean-Stark trap was drained and removed. Deionized water (1000 mL)was charged. The biphasic mixture was stirred for 10 minutes. Stirringwas stopped and the phases allowed to separate. The lower aqueous phasewas siphoned off and discarded. A 10 wt % aqueous solution of sodiumbicarbonate (1000 mL) was charged to the reaction mixture. The mixturewas stirred for 10 minutes. The reaction mixture was tested with pHpaper to ensure the pH of the solution was greater than 7. Water (500mL) was added to the reaction mixture. The stirring was stopped and thephases allowed to separate. The lower aqueous layer was siphoned off anddiscarded. The reaction mixture was washed with another 500 mL portionof deionized water. The reactor was set up for atmospheric distillationinto a tared 5 L receiver. The mixture was distilled until the pottemperature rose to between 140 and 150° C. The distillation wasswitched from atmospheric distillation to vacuum distillation. Thepressure in the distillation setup was slowly lowered to 100 mmHg. Thepot temperature fell and the remaining n-butanol and n-butyl ether (areaction byproduct) distilled off. The heating was stopped and thereaction mixture allowed to cool to ambient temperature. The vacuum wasbroken with dry nitrogen. The crude butyl ester was transferred to a 5 Lpot flask of a vacuum distillation setup. The crude butyl ester wasdistilled at a pressure between 0.2 and 0.5 mmHg. The forerun collectedat a head temperature of <40° C. was discarded. The butyl4-chloro-2-hydroxybenzoate fraction was collected at a head temperaturebetween 104 and 112° C. This fraction had a weight of 2559 g. The yieldwas 96%.

[0049] A 22 L, five neck, round bottom flask was equipped with anoverhead stirrer, reflux condenser, thermocouple temperature read out,and a heating mantle. The reactor was purged with nitrogen. Butyl4-chloro-2-hydroxybenzoate (2559 g, 11.2 moles) and reagent methanol(10,000 mL) were charged to the reaction flask, and the contents werestirred until a solution was obtained. The reaction mixture was filteredthrough a Buchner funnel and returned to the reactor. The stirring ratewas increased, and gaseous ammonia was added rapidly to the headspace ofthe reactor. The ammonia gas addition was continued until thetemperature of the reactor reached 45° C. The addition of the ammoniawas suspended and the agitation rate lowered. The reaction was allowedto cool to ambient temperature. Ammonia gas addition, as describedabove, was repeated until the reaction was complete as indicated byliquid chromatography. Seven ammonia charges over five days were neededto complete the reaction. Approximately half of the solvent was removedby atmospheric distillation. The reaction mixture was cooled to ambienttemperature and 5 L of deionized water was added. Concentratedhydrochloric acid (approximately 500 mL) was added slowly to the reactoruntil the pH of the reaction mixture was between 4 and 5. The resultingprecipitate was collected by vacuum filtration through a large sinteredglass funnel. The product filter cake was washed with 2000 mL ofdeionized water, and dried at 50° C. for 32 hours to give 1797 g of4-chloro-2-hydroxybenzamide. The yield was 94%.

[0050] A 22 L, five neck, round bottom flask was equipped with anoverhead stirrer, reflux condenser, addition funnel, thermocoupletemperature read out, and a heating mantle. The reactor was purged withnitrogen. Acetonitrile (4700 mL) and 4-chloro-2-hydroxybenzamide (1782g, 10.4 mol) were charged to the reaction flask and the stirring wasstarted. Pyridine (1133 mL, 14.0 mol) was charged to the reactor. Theresulting reaction slurry was cooled to less than 10° C. with an icebath. Ethyl chloroformate (1091 mL, 1237 g, 11.4 mol) was placed in theaddition funnel and charged slowly to the stirred reaction mixture suchthat the temperature of the reaction mixture did not exceed 15° C.during the addition. The temperature of the reaction mixture was heldbetween 10 and 15° C. for 30 minutes after the ethyl chloroformateaddition was complete. The ice bath was removed, and the reactionmixture was warmed to ambient temperature. The reaction mixture was thenslowly heated to reflux and held at that temperature for 18 hours.Liquid chromatographic analysis of the reaction mixture indicated thatthe reaction was only 80% complete. Approximately half of the solventwas removed by atmospheric distillation. The reaction mixture was cooledfirst to ambient temperature and then to <10° C. with an ice bath.Additional pyridine (215 mL, 2.65 mol) was added to the reactionmixture. Ethyl chloroformate (235 g, 2.17 mol) was added slowly via anaddition funnel to the cold reaction mixture. The reaction mixture washeld between 10 and 15° C. for 30 minutes after the ethyl chloroformateaddition was complete. The ice bath was removed, and the reactionmixture was warmed to ambient temperature. The reaction mixture was thenslowly heated to reflux and held at that temperature for 18 hours, afterwhich time liquid chromatographic analysis indicated that the reactionwas complete. The reaction mixture was cooled first to ambienttemperature and then to <10° C. with an ice bath. Water (1600 mL) wasadded slowly via an addition funnel and the resulting slurry held at<10° C. for 90 minutes. The solid product was collected by vacuumfiltration through a large sintered glass funnel. The product filtercake was washed with deionized water and vacuum dried at 50° C. for 18hours to give 1914 g of 7-chloro-2H-1,3-benzoxazine-2,4(3H)-dione as atan solid. The yield was 83%.

[0051] A 22 L, five neck, round bottom flask was equipped with anoverhead stirrer, reflux condenser, thermocouple temperature read out,and heating mantle. The following reaction was run under a dry nitrogenatmosphere. 7-Chloro-2H-1,3-benzoxazine-2,4(3H)-dione (1904 g, 9.64mol), ethyl 4-bromobutyrate (1313 mL, 9.18 mol), andN,N-dimethylacetamide (4700 mL) were charged under a nitrogen purge. Thereaction mixture was heated to 70° C. Sodium carbonate (1119 g, 10.55mol) was charged to the clear solution in five equal portions overapproximately 40 minutes. The reaction mixture was held at 70° C.overnight. The reaction was cooled to 55° C. The inorganic solids wereremoved by vacuum filtration through a sintered glass funnel. Thereaction flask was rinsed with 2B-ethanol (2000 mL) and this rinse usedto wash the filter cake. The reaction flask was cleaned with deionizedwater. The filtrate was returned to the clean reaction flask. Thefiltrate was cooled in an ice bath. Deionized water (9400 mL) was addedslowly with an addition funnel. The chilled mixture was allowed to stirovernight. The resulting solids were recovered by vacuum filtrationthrough a sintered glass funnel. The product cake was washed withdeionized water. The ethyl3-(4-butanoate)-7-chloro-2H-1,3-benzoxazine-2,4-(3H)-dione had a weightof 2476.0 g. The yield was 82.2%.

[0052] A 12 L, stainless steel reactor was equipped with an overheadstirrer, reflux condenser, thermocouple temperature read out, additionfunnel, and heating mantle. The following reaction was run under a drynitrogen atmosphere. Water (3 L) and ethyl3-(4-butanoate)-7-chloro-2H-1,3-benzoxazine-2,4-(3H)-dione (1118 g, 3.58mol) were charged to the reactor and stirring was started. A solution ofsodium hydroxide (574 g, 4.34 mol) in-water (2 L) was added slowly tothe reaction slurry. The reaction was heated to 70° C. for 6 hours, andthen allowed to cool slowly to ambient temperature. The reaction mixturewas filtered through a Buchner funnel.

[0053] A 22 L five neck round bottom flask was equipped with an overheadstirrer, reflux condenser, thermocouple temperature read out, and anaddition funnel. Deionized water (1880 mL) and concentrated hydrochloricacid (1197 g, 12.04 mol) were charged to the reactor. The hydrolysatefrom above was added slowly via addition funnel to the acid solution.The pH of the resulting slurry was adjusted to 3 by adding additionalhydrochloric acid (160 mL, 1.61 mol) The product solids were collectedby filtration through a sintered glass funnel and dried in a vacuum ovenat 50° C. for 24 hours to give 1109.3 g of4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid as an off whitesolid. The yield was quantitative.

EXAMPLE 1d

[0054] Preparation of Anhydrous Sodium4-[(2-Hydroxybenzoyl)amino]butanoate

[0055] A 22 L, five neck round bottom flask, was equipped with anoverhead stirrer, reflux condenser, thermocouple temperature read out,and heating mantle. The following reaction was run under a dry nitrogenatmosphere. Reagent acetone (13000 mL) and4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (500.0 g, 1.94 mol)were charged to the reactor and stirring was started. The reactionslurry was heated to 50° C. until a hazy brown solution was obtained.The warm solution was pumped through a warm pressure filter dressed withWhatman #1 paper into a clean 22 L reactor. The clear yellow filtratewas heated to 50° C. while stirring. Sodium hydroxide solution (50%aqueous; 155 g, 1.94 mol) was charged to the reactor while maintainingvigorous agitation. After the base addition was complete, the reactorwas heated to reflux (60° C.) for 2.5 hours and then allowed to coolslowly to ambient temperature. The product was isolated by vacuumfiltration through a sintered glass funnel and dried in a vacuum oven at50° C. for 24 hours to give 527.3 g of sodium4-[(2-hydroxybenzoyl)amino]butanoate as an off-white solid. The yieldwas 97.2%.

EXAMPLE 1e

[0056] Preparation of Sodium 4-[(2-Hydroxybenzoyl)-amino]butanoate monohydrate

[0057] A 22 L flask was equipped with an overhead stirrer. Deionizedwater (2000 mL) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid(380.0 g, 1.47 mol) were added and stirring was started. A solution ofsodium hydroxide (59.0 g, 1.48 mol) in water (500 mL) was added to thereactor. Water (1500 mL) was added to the reactor, and the resultingslurry was heated until a complete solution was obtained. The reactionmixture was cooled to ambient temperature, and then concentrated todryness under reduced pressure. The resulting solids were scraped fromthe flask and vacuum dried at 50° C. to give 401.2 g of sodium4-[(2-hydroxybenzoyl)amino]butanoate as an off-white solid. The yieldwas 96.9%.

EXAMPLE 1f

[0058] Preparation of Sodium 4-[(2-Hydroxybenzoyl)-amino]butanoateThrough the Isopropanol Solvate

[0059] A one liter, four neck round bottom flask was equipped with anoverhead stirrer, reflux condenser, thermocouple temperature read out,and heating mantle. The following reaction was run under a dry nitrogenatmosphere. Isopropanol (400 mL) and4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (25.0 g, 0.09 mol)were charged to the reactor and stirring was started. The reactionslurry was heated to 50° C. until a hazy brown solution was obtained.The warm solution was filtered through a warm pressure filter dressedwith Whatman #1 paper into a clean 1 L reactor. The clear yellowfiltrate was heated to 62° C. while stirring. Sodium hydroxide solution(50% aqueous; 7.2 g, 0.09 mol) was charged to the reactor whilemaintaining vigorous agitation. After the base addition was complete,the reactor was heated to reflux (72° C.) and then allowed to coolslowly to ambient temperature. The product was isolated by vacuumfiltration through a sintered glass funnel and vacuum dried at 50° C.for 24 hours to give 23.16 g of sodium4-[(2-hydroxybenzoyl)amino]butanoate as an off-white solid. The yieldwas 92%.

EXAMPLE 1g

[0060] Capsule Preparation

[0061] Capsules for primate dosing containing the monosodium salt ofcompound 1 (as prepared in example 1d) and insulin were prepared asfollows. The compound 1 monosodium salt and QA307X zinc insulin crystalshuman: proinsulin derived (recombinant DNA origin) (available fromEli-Lilly & Co. of Indianapolis, Ind.) were first screened through a 35mesh Tyler standard sieve and the required amount weighed. Screenedcompound 1 monosodium salt and insulin were blended using geometricsieving method in a suitably sized glass mortar. The materials in themortar were mixed well with a glass pestle. A spatula was used forscrapping the sides of the mortar. The resulting formulation wastransferred to a plastic weigh boat for capsule filling. The formulationwas hand packaged into size #0 Torpac hard gelatin capsules (availablefrom Torpac, Inc. of Fairfield, N.J.). Each capsule fill weight wasdependent on the individual animal weight. Capsules doses of compound 1were 100 mg/kg, 75 mg/kg and 50 mg/kg (as monosodium salt). Capsuledoses of insulin were 0.25 to 0.5 mg per kg.

EXAMPLE 2

[0062] Insulin—Oral Delivery

[0063] A. Rat Studies Oral dosing (PO) compositions of delivery agentcompound (prepared as in Example 1a or 1b as indicated below) and zinchuman recombinant insulin (available from Calbiochem-Novabiochem Corp.,La Jolla, Calif. (Catalog # 407694)) were prepared in deionized water.Typically, 500 mg of delivery agent compound was added to 1.5 ml ofwater. The free acid of the delivery agent compound was converted to thesodium salt by stirring the resultant solution and adding one equivalentof sodium hydroxide. The solution was vortexed, then heated (about 37°C.) and sonicated. The pH was adjusted to about 7 to 8.5 with NaOH orHCl. Additional NaOH was added, if necessary, to achieve uniformsolubility, and the pH re-adjusted. (For example, for compound 1a, atotal of 258.5 ml 10N NaOH was added to 501 mg compound in 1.5 ml water,final pH 7.73.) Water was then added to bring the total volume to about2.4 ml and vortexed. About 1.25 mg insulin from an insulin stocksolution (15 mg/ml made from 0.5409 g insulin and 18 ml deionized water,adjusting with HCl and NaOH to pH 8.15 and to obtain a clear solutionusing 40 ml concentrated HCl, 25 ml 10N NaOH and 50 ml 1N NaOH) wasadded to the solution and mixed by inverting. The final delivery agentcompound dose, insulin dose and dose volume amounts are listed below inTable 1.

[0064] The dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between about 200-250 g were fasted for 24hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5mg/kg) 15 minutes prior to dosing and again as needed to maintainanesthesia. A dosing group of five animals was administered one of thedosing solutions. For oral dosing, an 11 cm Rusch 8 French catheter wasadapted to a 1 ml syringe with a pipette tip. The syringe was filledwith dosing solution by drawing the solution through the catheter, whichwas then wiped dry. The catheter was placed down the esophagus leaving 1cm of tubing past the incisors. Solution was administered by pressingthe syringe plunger.

[0065] Blood samples were collected serially from the tail artery,typically at time=15, 30, 60, 120 and 180 minutes after administration.Serum insulin levels were determined with an Insulin ELISA Test Kit (Kit# DSL-10-1600 from Diagnostic Systems Laboratories, Inc., Webster,Tex.), modifying the standard protocol in order to optimize thesensitivity and linear range of the standard curve for the volumes andconcentrations of the samples used in the present protocol. Serum humaninsulin concentrations (μU/ml) were measured for each time point foreach of the five animals in each dosing group. The five values for eachtime point were averaged and the results plotted as serum insulinconcentration versus time. The maximum (peak) and the area under thecurve (AUC) are reported below in Table 1. Previous experiments revealedno measurable levels of human insulin following oral dosing with humaninsulin alone. TABLE 1 Insulin-Oral Delivery Mean Peak volume CompoundInsulin Serum Human dose Dose Dose Insulin Compound (ml/kg) (mg/kg)(mg/kg) (μU/ml ± SE) AUC 1a 1.0 200 0.5 1457 ± 268 58935 1b 1.0 200 0.5183 ± 89 8674 1b 1.0 200 0.5 136 ± 52 5533 1b 1.0 200 0.5 205 ± 61 79961b 1.0 200 0.5 139 ± 43 5271

[0066] B. Monkey Studies

[0067] All animal protocols adhered to the “Principles of LaboratoryAnimal Care” and were Institutional Animal Care and Use Committee(IACUC) approved.

[0068] The dosing protocol for administering the capsules to each animalwas as follows. Baseline plasma samples were obtained from the animalsprior to dosing. Groups of four cynomolgus monkeys, two males and twofemales, weighing 2-3 kg were fasted for 4 hours prior to dosing and upto 2 hours after dosing. The animals were anesthetized with anintramuscular injection of 10 mg/kg ketamine hydrochloride immediatelyprior to dosing. Each animal was administered varying doses of compound1 (25-100 mg/kg) in combination with varying doses of insulin 0.25-0.5mg/kg insulin as 1 capsule. Water was available throughtout the dosingperiod and 400 ml of juice was made available to the animal overnightprior to dosing and throughout the dosing period. The animal wasrestrained in a sling restraint. A capsule was placed into a pill gun,which is a plastic tool with a cocket plunger and split rubber tip toaccommodate a capsule. The pill gun was inserted into the espophagus ofthe animal. The plunger of the pill gun was pressed to push the capsuleout of the rubber tip into the espophagus. The pill gun was thenretracted. The animals mouth was held closed and approximately 5 mlreverse osmosis water was administered into the mouth from the side toinduce a swallowing reflex. The throat of the animal was rubbed furtherto induce the swallowing reflex.

[0069] Citrated blood samples (1 mL each) were collected by venipuncturefrom an appropriate vein at 1 hour before dosing and at 10, 20, 30, 40,and 50 minutes and 1, 1.5, 2, 3, 4, and 6 hours after dosing. Eachharvested plasma sample was divided into two portions. One portion wasfrozen at −80° C. and shipped to another location for insulin assay. Theother portion was used in the blood glucose assay. Four monkeys alsoreceived insulin subcutaneously (0.02 mg/kg). Blood samples werecollected and analyzed as described above.

[0070] Insulin Assays. Serum insulin levels were measured using theInsulin ELISA Test Kit (DSL, Webster, Tex.).

[0071] Glucose Assays. Blood glucose measurements were performed usingONETOUCH® Glucose Monitoring System from Live Scan Inc., Newtown, Pa.

[0072] The results are shown in Table 1A below. TABLE 1A Insulin - OralDelivery to Monkeys Mean Peak Compound Insulin Serum Human Mean PeakBlood Com- Dose Dose Insulin Glucose Reduction pound (mg/kg) (mg/kg)(μU/ml ± SE) (μU/ml ± SE) 1d 100 0.5 91.4 ± 45   52.3 ± 5.3  1d 50 0.5124.1 ± 51.95  −61 ± 12.7 1d 25 0.5 87.14 ± 53.85 −28.75 ± 21.59   1d 250.25 36.35 ± 32.3     −19 ± 10.21

EXAMPLE 3

[0073] Cromolyn—Oral Delivery

[0074] Dosing solutions containing a delivery agent compound (preparedas in Example 1b) and cromolyn, disodium salt (cromolyn) (Sigma,Milwaukee, Wis.) were prepared in deionized water. The free acid of thedelivery agent compound was converted to the sodium salt with oneequivalent of sodium hydroxide. This mixture was vortexed and placed ina sonicator (about 37° C.). The pH was adjusted to about 7-7.5 withaqueous NaOH. Additional NaOH was added, if necessary, to achieveuniform solubility, and the pH re-adjusted. The mixture was vortexed toproduce a uniform solution, also using sonication and heat if necessary.The delivery agent compound solution was mixed with cromolyn from astock solution (175 mg cromolyn/ml in deionized water, pH adjusted, ifnecessary, with NaOH or HCl to about 7.0, stock solution stored frozenwrapped in foil, then thawed and heated to about 30° C. before using).The mixture was vortexed to produce a uniform solution, also usingsonication and heat if necessary. The pH was adjusted to about 7-7.5with aqueous NaOH. The solution was then diluted with water to thedesired volume (usually 2.0 ml) and concentration and stored wrapped infoil before use. The final delivery agent compound and cromolyn doses,and the dose volumes are listed below in Table 2.

[0075] The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between 200-250 g were fasted for 24 hoursand were anesthetized with ketamine (44 mg/kg) and chlorpromazine (1.5mg/kg) 15 minutes prior to dosing and again as needed to maintainanesthesia. A dosing group of five animals was administered one of thedosing solutions. An 11 cm Rusch 8 French catheter was adapted to a 1 mlsyringe with a pipette tip. The syringe was filled with dosing solutionby drawing the solution through the catheter, which was then wiped dry.The catheter was placed down the esophagus leaving 1 cm of tubing pastthe incisors. Solution was administered by pressing the syringe plunger.

[0076] Blood samples were collected via the tail artery, typically at0.25, 0.5, 1.0 and 1.5 hours after dosing. Serum cromolyn concentrationswere measured by HPLC. Samples were prepared as follows: 100 μl serumwas combined with 100 μl 3N HCl and 300 μl ethyl acetate in an eppendorftube. The tube was vortexed for 10 minutes and then centrifuged for 10minutes at 10,000 rpm. 200 μl ethyl acetate layer was transferred to aneppendorf tube containing 67 μl 0.1 M phosphate buffer. The tube wasvortexed for 10 minutes and then centrifuged for 10 minutes at 10,000rpm. The phosphate buffer layer was then transferred to an HPLC vial andinjected into the HPLC (column=Keystone Exsil Amino 150×2 mm i.d., 5 μm,100 Å (Keystone Scientific Products, Inc.); mobile phase=35% buffer(68mM KH₂PO₄ adjusted to pH 3.0 with 85% H₃PO₄)/65% acetonitrile; injectionvolume=10 μl; flow rate=0.30 ml/minute; cromolyn retention time=5.5minutes; absorbance detected at 240 nm). Previous studies indicatedbaseline values of about zero.

[0077] Results from the animals in each group were averaged for eachtime point and the highest of these averages (i.e., mean peak serumcromolyn concentration) is reported below in Table 2. TABLE 2 Cromolyn -Oral Delivery Mean Peak volume Compound Cromolyn serum dose Dose Dose[cromolyn] ± Compound (ml/kg) (mg/kg) (mg/kg) SD (SE) 1b 1 200 25 0.70 ±0.36 (0.16)

EXAMPLE 4

[0078] Recombinant Human Growth Hormone (rhGH)—Oral Delivery

[0079] Oral gavage (PO) dosing solutions of delivery agent compound(prepared as in Example 1a or 1b as indicated in Table 3 below) and rhGHwere prepared in phosphate buffer. The free acid of the delivery agentcompound was converted to the sodium salt with one equivalent of sodiumhydroxide. Typically, a solution of the compound was prepared inphosphate buffer and stirred, adding one equivalent of sodium hydroxide(1.0 N) when making the sodium salt. Additional NaOH was added, ifnecessary, to achieve uniform solubility, and the pH re-adjusted. Thefinal dosing solutions were prepared by mixing the compound solutionwith an rhGH stock solution (15 mg rhGH/ml made by mixing as powders 15mg rhGH, 75 mg D-mannitol, 15 mg glycine and 3.39 mg dibasic sodiumphosphate, then diluting with 2% glycerol) and diluting to the desiredvolume (usually 3.0 ml). The compound and rhGH doses and the dosevolumes are listed below in Table 3.

[0080] The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between 200-250 g were fasted for 24 hoursand administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15minutes prior to dosing and again as needed to maintain anesthesia. Adosing group of five animals was administered one of the dosingsolutions. An 11 cm Rusch 8 French catheter was adapted to a 1 mlsyringe with a pipette tip. The syringe was filled with dosing solutionby drawing the solution through the catheter, which was then wiped dry.The catheter was placed down the esophagus leaving 1 cm of tubing pastthe incisors. Solution was administered by pressing the syringe plunger.

[0081] Blood samples were collected serially from the tail artery,typically at time=15, 30, 45 and 60 minutes after administration. SerumrHGH concentrations were quantified by an rHGH immunoassay test kit (Kit# K1F4015 from Genzyme Corporation Inc., Cambridge, Mass.). Previousstudies indicated baseline values of about zero.

[0082] Results from the animals in each group were averaged for eachtime point. The maximum of these averages (i.e., the mean peak serumrhGH concentration) is reported below in Table 3. (In the cases where nostandard deviation (SD) or standard error (SE) is given below, the fivesamples from each time period were pooled prior to assaying.) TABLE 3rhGH - Oral Delivery Volume Compound rhGH Mean Peak dose Dose Dose Serum[rhGH] ± SD Compound (ml/kg) (mg/kg) (mg/kg) (SE) (ng/ml) 1a 1 200 399.35 1a 1 200 3 42.62 1b 1 200 3 84.01 ± 73.57 (32.90) 1b 1 200 3 50.44± 34.13 (15.26)

EXAMPLE 5

[0083] Interferon—Oral Delivery

[0084] Dosing solutions of delivery agent compound (prepared as inExample 1b) and human interferon (IFN) were prepared in deionized water.The free acid of the delivery agent compound was converted to the sodiumsalt with one equivalent of sodium hydroxide. Typically, a solution ofthe delivery agent compound was prepared in water and stirred, addingone equivalent of sodium hydroxide (1.0 N) when making the sodium salt.This mixture was vortexed and placed in a sonicator (about 37° C.). ThepH was adjusted to about 7.0 to 8.5 with aqueous NaOH. The mixture wasvortexed to produce a uniform suspension or solution, also usingsonication and heat if necessary. Additional NaOH was added, ifnecessary, to achieve uniform solubility, and the pH re-adjusted. Thedelivery agent compound solution was mixed with an IFN stock solution(about 22.0 to 27.5 mg/ml in phosphate buffered saline) and diluted tothe desired volume (usually 3.0 ml). The final delivery agent compoundand IFN doses, and the dose volumes are listed below in Table 4.

[0085] The typical dosing and sampling protocols were as follows. MaleSprague-Dawley rats weighing between 200-250 g were fasted for 24 hoursand administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15minutes prior to dosing and again as needed to maintain anesthesia. Adosing group of five animals was administered one of the dosingsolutions. An 11 cm Rusch 8 French catheter was adapted to a 1 mlsyringe with a pipette tip. The syringe was filled with dosing solutionby drawing the solution through the catheter, which was then wiped dry.The catheter was placed down the esophagus leaving 1 cm of tubing pastthe incisors. Solution was administered by pressing the syringe plunger.

[0086] Blood samples were collected serially from the tail artery,typically at time=0, 15, 30, 45, 60 and 90 minutes after administration.Serum IFN concentrations were quantified using Cytoscreen ImmunoassayKit for human IFN-alpha (catalog # KHC4012 from Biosource International,Camarillo, Calif.). Previous studies indicated baseline values of aboutzero. Results from the animals in each group were averaged for each timepoint. The maximum of these averages (i.e., the mean peak serum IFNconcentration) is reported below in Table 4. TABLE 4 Interferon - OralDelivery Mean Peak Volume Compound IFN Serum [IFN] dose Dose Dose(ng/ml) ± Compound (ml/kg) (mg/kg) (mg/kg) SD (SE) 1b 1.0 200 1.0 17.80± 13.52 (6.05)

[0087] The above-mentioned patents, applications, test methods, andpublications are hereby incorporated by reference in their entirety.

[0088] Many variations of the present invention will suggest themselvesto those skilled in the art in light of the above detailed description.All such obvious variations are within the fully intended scope of theappended claims.

What is claimed is:
 1. A compound of the formula

and salts thereof.
 2. A composition comprising: (A) an active agent; and(B) a compound having the formula

 a salt thereof, or a mixture thereof.
 3. The composition of claim 2,wherein the active agent is selected from the group consisting of abiologically active agent, a chemically active agent, and a combinationthereof.
 4. The composition of claim 3, wherein the biologically activeagent comprises at least one protein, polypeptide, peptide, hormone,polysaccharide, mucopolysaccharide, carbohydrate, or lipid.
 5. Thecomposition of claim 3, wherein the biologically active agent isselected from the group consisting of: growth hormones, human growthhormones, recombinant human growth hormones, bovine growth hormones,porcine growth hormones, growth hormone-releasing hormones, interferons,α-interferon, β-interferon, γ-interferon, interleukin-1, interleukin-2,insulin, porcine insulin, bovine insulin, human insulin, humanrecombinant insulin, insulin-like growth factor, insulin-like growthfactor −1, heparin, unfractionated heparin, heparinoids, dermatans,chondroitins, low molecular weight heparin, very low molecular weightheparin, ultra low molecular weight heparin, calcitonin, salmoncalcitonin, eel calcitonin, human calcitonin; erythropoietin (EPO),atrial naturetic factor, antigens, monoclonal antibodies, somatostatin,protease inhibitors, adrenocorticotropin, gonadotropin releasinghormone, oxytocin, leutinizing-hormone-releasing-hormone, folliclestimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim,prostaglandins, cyclosporin, vasopressin, cromolyn sodium, sodiumchromoglycate, disodium chromoglycate, vancomycin, desferrioxamine,parathyroid hormone, fragments of parathyroid hormone, antimicrobials,anti-fungal agents, vitamins; analogs, fragments, mimetics andpolyethylene glycol-modified derivatives of these compounds; and anycombination thereof.
 6. The composition of claim 3, wherein thebiologically active agent comprises insulin, human growth hormone,interferon, cromolyn sodium or combinations thereof.
 7. The compositionof claim 3, wherein the biologically active agent comprises insulin. 8.The composition of claim 3, wherein the biologically active agentcomprises interferon.
 9. A dosage unit form comprising: (A) thecomposition of claim 2; and (B) (a) an excipient (b) a diluent, (c) adisintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g) adosing vehicle, or (h) any combination thereof.
 10. The dosage unit formof claim 9, wherein the active agent is selected from the groupconsisting of a biologically active agent, a chemically active agent,and a combination thereof.
 11. The dosage unit form of claim 10, whereinthe biologically active agent comprises at least one protein,polypeptide,.peptide, hormone, polysaccharide, mucopolysaccharide,carbohydrate, or lipid.
 12. The dosage unit form of claim 10, whereinthe biologically active agent is selected from the group consisting of:growth hormones, human growth hormones, recombinant human growthhormones, bovine growth hormones, porcine growth hormones, growthhormone-releasing hormones, interferons, α-interferon, β-interferon,γ-interferon, interleukin-1, interleukin-2, insulin, porcine insulin,bovine insulin, human insulin, human recombinant insulin, insulin-likegrowth factor, insulin-like growth factor −1, heparin, unfractionatedheparin, heparinoids, dermatans, chondroitins, low molecular weightheparin, very low molecular weight heparin, ultra low molecular weightheparin, calcitonin, salmon calcitonin, eel calcitonin, humancalcitonin; erythropoietin, atrial naturetic factor, antigens,monoclonal antibodies, somatostatin, protease inhibitors,adrenocorticotropin, gonadotropin releasing hormone, oxytocin,leutinizing-hormone-releasing-hormone, follicle stimulating hormone,glucocerebrosidase, thrombopoietin, filgrastim, prostaglandins,cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate,disodium chromoglycate, vancomycin, desferrioxamine, parathyroidhormone, fragments of parathyroid hormone, antimicrobials, anti-fungalagents, vitamins; analogs, fragments, mimetics and polyethyleneglycol-modified derivatives of these compounds; and any combinationthereof.
 13. The dosage unit form of claim 10, wherein the biologicallyactive agent comprises insulin, human growth hormone, interferon,cromolyn sodium or combinations thereof.
 14. The dosage unit form ofclaim 9, wherein the active agent comprises insulin.
 15. The dosage unitform of claim 9, wherein the active agent comprises interferon.
 16. Thedosage unit form of claim 9, wherein the dosage unit form is in the formof a tablet, a capsule, a particle, a powder, a sachet, or a liquid. 17.The dosage unit form of claim 9, wherein the dosing vehicle is a liquidselected from the group consisting of water, 25% aqueous propyleneglycol, phosphate buffer, 1,2-propane diol, ethanol, and any combinationthereof.
 18. A method for administering a biologically-active agent toan animal in need of the agent, the method comprising administeringorally to the animal the composition of claim
 3. 19. A method forpreparing a composition comprising mixing: (A) at least one activeagent; (B) the compound of claim 1; and (C) optionally, a dosingvehicle.
 20. A method of treating a disease comprising administering thecomposition of claim 3 to an animal in need thereof.